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RNA Sequencing Identifies Dysregulation of the Human Pancreatic Islet Transcriptome by the Saturated Fatty Acid Palmitate

Cnop, Miriam, Abdulkarim, Baroj, Bottu, Guy, Cunha, Daniel A., Igoillo-Esteve, Mariana, Masini, Matilde, Turatsinze, Jean-Valery, Griebel, Thasso, Villate, Olatz, Santin, Izortze, Bugliani, Marco, Ladriere, Laurence, Marselli, Lorella, McCarthy, Mark I., Marchetti, Piero, Sammeth, Michael, Eizirik, Décio L.·2014·Diabetes
DOI 10.2337/db13-1383
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Abstract

Pancreatic β-cell dysfunction and death are central in the pathogenesis of type 2 diabetes (T2D). Saturated fatty acids cause β-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy, and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling β-cell phenotype, including PAX4 and GATA6. Fifty-nine T2D candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis of transcription factor binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA, and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced β-cell dysfunction and death. The data point to cross talk between metabolic stress and candidate genes at the β-cell level.

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Image 1
CC-BY-NC-ND · From the PDF
Figure 1 GWAS-based T2D candidate genes are well expressed in human islets. A : Expression levels of transcripts of T2D candidate genes with an expression of RPKM > 1 (i.e., 80% of currently known T2D candidate genes). Red bars indicate signi fi cantly upregulated transcripts and green bars, downregulated transcripts. B : Box plot of median expression levels of all T2D candidate genes compared with all genes, a random set of 60 genes, or the candidate genes associated with ulcerative colitis or body height. The numbers above the fi gure show the percentage of genes considered present (RPKM > 1) and the P value for the Fisher exact test of the selected gene set vs. all genes. The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively; the whiskers mark the highest and the lowest data point still within 1.5 interquartile range above the 75th percentile and 1.5 interquartile range below the 25th percentile, respectively; and the circles indicate outliers.
Figure 1 GWAS-based T2D candidate genes are well expressed in human islets. A : Expression levels of transcripts of T2D candidate genes with an expression of RPKM > 1 (i.e., 80% of currently known T2D candidate genes). Red bars indicate signi fi cantly upregulated transcripts and green bars, downregulated transcripts. B : Box plot of median expression levels of all T2D candidate genes compared with all genes, a random set of 60 genes, or the candidate genes associated with ulcerative colitis or body height. The numbers above the fi gure show the percentage of genes considered present (RPKM > 1) and the P value for the Fisher exact test of the selected gene set vs. all genes. The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively; the whiskers mark the highest and the lowest data point still within 1.5 interquartile range above the 75th percentile and 1.5 interquartile range below the 25th percentile, respectively; and the circles indicate outliers.CC-BY-NC-ND · From the PDF
Image 3
CC-BY-NC-ND · From the PDF
Figure 3 Impact of palmitate on human islet metabolic pathways and protein synthesis, ER stress response, and protein degradation pathways. A : Manual curation of palmitate-modi fi ed human islet transcripts that may affect metabolic pathways pertaining to the Krebs cycle, oxidative phosphorylation, amino acid catabolism, FFA metabolism, ceramide synthesis and metabolism, and triglyceride synthesis. B : Manual curation of palmitate-modi fi ed human islet transcripts that may affect protein synthesis and processing, pertaining to tRNA synthesis, protein translation, and hormone processing pathways, as well as branches of the ER stress response controlled by IRE1, PERK, and ATF6, ER quality control (QC), and ER-associated degradation (ERAD), ubiquitination, proteasomal degradation, autophagy, and lysosomal function. Upregulated genes are shown in red and downregulated genes in green.
Figure 3 Impact of palmitate on human islet metabolic pathways and protein synthesis, ER stress response, and protein degradation pathways. A : Manual curation of palmitate-modi fi ed human islet transcripts that may affect metabolic pathways pertaining to the Krebs cycle, oxidative phosphorylation, amino acid catabolism, FFA metabolism, ceramide synthesis and metabolism, and triglyceride synthesis. B : Manual curation of palmitate-modi fi ed human islet transcripts that may affect protein synthesis and processing, pertaining to tRNA synthesis, protein translation, and hormone processing pathways, as well as branches of the ER stress response controlled by IRE1, PERK, and ATF6, ER quality control (QC), and ER-associated degradation (ERAD), ubiquitination, proteasomal degradation, autophagy, and lysosomal function. Upregulated genes are shown in red and downregulated genes in green.CC-BY-NC-ND · From the PDF
Figure 4 DAVID analysis of palmitate-modi fi ed genes in human islets. RNA-seq data of transcripts upregulated ( A ) or downregulated ( B ) by palmitate or with modi fi ed alternative splicing ( C ) were analyzed for term enrichment against UCSC_TFBS. The length of the bars indicates the signi fi cance of the overrepresentation of potential binding sites for the indicated transcription factors in the modi fi ed genes, expressed as minus the logarithm of the probability that a set of genes taken at random from the human genome would pop up the same entries. Only the 30 top entries are displayed. The vertical line indicates a probability threshold of 0.05, corresponding to a 2 log(BH P value) of 1.3.
Figure 4 DAVID analysis of palmitate-modi fi ed genes in human islets. RNA-seq data of transcripts upregulated ( A ) or downregulated ( B ) by palmitate or with modi fi ed alternative splicing ( C ) were analyzed for term enrichment against UCSC_TFBS. The length of the bars indicates the signi fi cance of the overrepresentation of potential binding sites for the indicated transcription factors in the modi fi ed genes, expressed as minus the logarithm of the probability that a set of genes taken at random from the human genome would pop up the same entries. Only the 30 top entries are displayed. The vertical line indicates a probability threshold of 0.05, corresponding to a 2 log(BH P value) of 1.3.CC-BY-NC-ND · From the PDF
Figure 5 Role of novel ER stress transducers in lipotoxic b -cell death. A : RNA-seq data of CREB3 expression in fi ve human islet preparations exposed to palmitate for 48 h. B : CREB3 mRNA expression assessed by qRT-PCR in human islets exposed to 0.5 mmol/L oleate (OL), 0.5 mmol/L palmitate (PAL), 1 m mol/L thapsigargin (THA), 5 m g/mL tunicamycin (TU), or 0.1 m g/mL brefeldin A (BFA) ( n = 3 -6). CREB3 mRNA expression assessed by qRT-PCR ( C ) and apoptosis ( D ) in INS-1E cells transfected with control (negative) or two different CREB3 siRNAs and then treated with 0.5 mmol/L palmitate for 16 h ( n = 3). CREB3 mRNA expression ( E ) and apoptosis ( F ) in fl uorescenceactivated cell sorter -puri fi ed primary rat b -cells transfected with control or CREB3 siRNAs and then treated with 0.5 mmol/L palmitate for 24 h ( n = 3). G : Apoptosis in dispersed human islet cells transfected with control or CREB3 siRNAs and exposed to palmitate for 24 h. Individual data for two independent human islet preparations are shown. H : RNA-seq data of CREB3L3 expression in fi ve human islet preparations exposed to palmitate for 48 h. I : CREB3L3 mRNA expression assessed by qRT-PCR in human islets exposed to ER stressors as in panel B ( n = 3 -6). * P < 0.05 vs. control (CTL) or control cells transfected with negative siRNA; # P < 0.05 as indicated.
Figure 5 Role of novel ER stress transducers in lipotoxic b -cell death. A : RNA-seq data of CREB3 expression in fi ve human islet preparations exposed to palmitate for 48 h. B : CREB3 mRNA expression assessed by qRT-PCR in human islets exposed to 0.5 mmol/L oleate (OL), 0.5 mmol/L palmitate (PAL), 1 m mol/L thapsigargin (THA), 5 m g/mL tunicamycin (TU), or 0.1 m g/mL brefeldin A (BFA) ( n = 3 -6). CREB3 mRNA expression assessed by qRT-PCR ( C ) and apoptosis ( D ) in INS-1E cells transfected with control (negative) or two different CREB3 siRNAs and then treated with 0.5 mmol/L palmitate for 16 h ( n = 3). CREB3 mRNA expression ( E ) and apoptosis ( F ) in fl uorescenceactivated cell sorter -puri fi ed primary rat b -cells transfected with control or CREB3 siRNAs and then treated with 0.5 mmol/L palmitate for 24 h ( n = 3). G : Apoptosis in dispersed human islet cells transfected with control or CREB3 siRNAs and exposed to palmitate for 24 h. Individual data for two independent human islet preparations are shown. H : RNA-seq data of CREB3L3 expression in fi ve human islet preparations exposed to palmitate for 48 h. I : CREB3L3 mRNA expression assessed by qRT-PCR in human islets exposed to ER stressors as in panel B ( n = 3 -6). * P < 0.05 vs. control (CTL) or control cells transfected with negative siRNA; # P < 0.05 as indicated.CC-BY-NC-ND · From the PDF
Figure 6 Role of autophagy in lipotoxic b -cell death. LC3 conversion in INS-1E cells ( A and B ) and human islets ( C and D ) exposed to 0.5 mmol/L palmitate (PAL) for the indicated times ( n = 3 -4). B and D : LC3 I and II protein expression was quanti fi ed by densitometry and normalized to tubulin or b -actin or expressed as the ratio of LC3 II-to-I. E : Accumulation of autophagosomes (double membrane organelles containing rough ER and mitochondria and/or partially degraded ER; arrows) in human islets exposed to palmitate for 48 h. F : Apoptosis in INS-1E cells exposed to 0.5 mmol/L palmitate alone or in combination with the indicated concentrations (in m mol/L) of carbamazepine for 24 h ( n = 5 -7). G and H : LC3 conversion in human islets exposed to 0.5 mmol/L palmitate and/or 30 m mol/L carbamazepine for 24 h ( n = 3). I : Human islet cell death after 24 h exposure to palmitate and/or carbamazepine ( n = 4). * P < 0.05, ** P < 0.01, *** P < 0.001 vs. control (CTL); # P < 0.05 as indicated.
Figure 6 Role of autophagy in lipotoxic b -cell death. LC3 conversion in INS-1E cells ( A and B ) and human islets ( C and D ) exposed to 0.5 mmol/L palmitate (PAL) for the indicated times ( n = 3 -4). B and D : LC3 I and II protein expression was quanti fi ed by densitometry and normalized to tubulin or b -actin or expressed as the ratio of LC3 II-to-I. E : Accumulation of autophagosomes (double membrane organelles containing rough ER and mitochondria and/or partially degraded ER; arrows) in human islets exposed to palmitate for 48 h. F : Apoptosis in INS-1E cells exposed to 0.5 mmol/L palmitate alone or in combination with the indicated concentrations (in m mol/L) of carbamazepine for 24 h ( n = 5 -7). G and H : LC3 conversion in human islets exposed to 0.5 mmol/L palmitate and/or 30 m mol/L carbamazepine for 24 h ( n = 3). I : Human islet cell death after 24 h exposure to palmitate and/or carbamazepine ( n = 4). * P < 0.05, ** P < 0.01, *** P < 0.001 vs. control (CTL); # P < 0.05 as indicated.CC-BY-NC-ND · From the PDF
Figure 7 GATA6 inhibition by palmitate may contribute to b -cell death. GATA6 expression in fi ve human islet preparations exposed or not (CTL) to palmitate (PAL) for 48 h, measured by RNA-seq ( A ) and con fi rmed by qRT-PCR ( B ). C : GATA6 expression by qRT-PCR in fl uorescence-activated cell sorter -puri fi ed primary rat b -cells exposed to palmitate for 48 h ( n = 4). Primary rat b -cells ( D ), INS-1E cells ( E ), and dispersed human islets ( F ) were transfected with control siRNA (CTL) or two different siRNAs targeting GATA6 (#1 and #2). GATA6 mRNA expression was assessed by qRT-PCR ( n = 4 -7) ( D and F ) and protein expression by Western blot ( n = 3) ( E ). Apoptosis in primary rat b -cells ( G ) and dispersed rat ( H ) and human islets ( I ) transfected with control or GATA6 siRNAs and then exposed to palmitate for 24 h ( n = 3 -6). * P < 0.05, ** P < 0.01 vs. untreated cells; # P < 0.05, ## P < 0.01 as indicated.
Figure 7 GATA6 inhibition by palmitate may contribute to b -cell death. GATA6 expression in fi ve human islet preparations exposed or not (CTL) to palmitate (PAL) for 48 h, measured by RNA-seq ( A ) and con fi rmed by qRT-PCR ( B ). C : GATA6 expression by qRT-PCR in fl uorescence-activated cell sorter -puri fi ed primary rat b -cells exposed to palmitate for 48 h ( n = 4). Primary rat b -cells ( D ), INS-1E cells ( E ), and dispersed human islets ( F ) were transfected with control siRNA (CTL) or two different siRNAs targeting GATA6 (#1 and #2). GATA6 mRNA expression was assessed by qRT-PCR ( n = 4 -7) ( D and F ) and protein expression by Western blot ( n = 3) ( E ). Apoptosis in primary rat b -cells ( G ) and dispersed rat ( H ) and human islets ( I ) transfected with control or GATA6 siRNAs and then exposed to palmitate for 24 h ( n = 3 -6). * P < 0.05, ** P < 0.01 vs. untreated cells; # P < 0.05, ## P < 0.01 as indicated.CC-BY-NC-ND · From the PDF
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CC-BY-NC-ND · From the PDF

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Metadata

Authors
Cnop, M., Abdulkarim, B., Bottu, G., Cunha, D. A., Igoillo-Esteve, M., Masini, M., Turatsinze, J.-V., Griebel, T., Villate, O., Santin, I., Bugliani, M., Ladriere, L., Marselli, L., McCarthy, M. I., Marchetti, P., Sammeth, M., & Eizirik, D. L.
Affiliations
  • Laboratory of Experimental Medicine, ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
  • Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
  • Functional Bioinformatics, Centre Nacional d'Anàlisi Genòmica, Barcelona, Spain
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, U.K.
Venue
Diabetes
Publisher
American Diabetes Association
Published
2014-05-15
Volume
63
Issue
6
Pages
1978-1993
ISSN
  • 0012-1797
  • 1939-327X
DOI
10.2337/db13-1383
Cited by
250
References
7
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/3.0/ (vor, 2664 d)

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